Propofol (2,6-diisopropylphenol) is an injectable anesthetic, which has hypnotic properties and can be used to induce and maintain general anesthesia and sedation. Injectable anesthetics such as propofol are administered directly into the bloodstream. This results in a rapid onset of anesthesia influenced almost entirely by the rate at which the anesthetic agent crosses the blood-brain barrier. Therefore, the anesthetic agent must have sufficient lipid solubility to be able to cross this barrier and depress the relevant mechanisms of the brain. Propofol is poorly water-soluble and therefore is generally formulated as an emulsion. However, propofol containing emulsions have been shown to support microbial growth. Therefore it is desirable to formulate propofol emulsions in a manner in which microbial growth is prevented. Without a preservative in the formulation, any excess formulation must be thrown away within a few hours of its first use.
To overcome the contamination deficiencies found with propofol formulations, preservatives often added in the oil-in-water formulation to preserve its sterility and delay and retard the microorganism growth. U.S. Pat. Nos. 5,714,520, 5,731,355 and 5,731,356 disclose the use of EDTA in an amount sufficient to prevent no more than a 10-fold increase in microbial growth over 24 hours after adventitious extrinsic contamination with the microorganisms Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739), Pseudoinonas aeruginosa (ATCC 9027) and Candida albicans (ATCC 10231). Disodium EDTA (ethylenediamine tetraacetate) has been shown to delay, but not prevent, the onset of microbial growth in propofol emulsions. A propofol preparation for clinical use is commercially available as DIPRIVAN 1% Injection. In this formulation, a chelating or sequestering agent (i.e., ethylene diaminetetraacetic acid (EDTA)) is included in the propofol preparation. Unfortunately, formulations containing EDTA is not truly an antimicrobial preserved product under USP standards.
U.S. Pat. No. 6,150,423 discloses using benzyl alcohol as preservative against microbial growth. U.S. Pat. Nos. 6,140,373 and 6,140,374 discloses the use of a number of antimicrobial agents in propofol containing oil-in-water emulsions including combinations of EDTA and benzyl alcohol. However, addition of benzyl alcohol destroys the oil-in-water emulsion and therefore its use is restricted to formulation having a substantially phospholipid-free emulsifying agent.
U.S. Pat. No. 6,147,122 discloses a sterile oil-in-water emulsion of propofol and an amount of sodium metabisulfite. The amount of sodium metabisulfite in propofol administrated to patients requires careful monitoring not to exceed the limit set by the World Health Organization (WHO) (7.0 mg/kg as SO2) and the amount infused in total-parenteral-nutrition amino acid formulations, as well as during peritoneal dialysis. In addition, sodium metabisulfite is known for its potential allergy and hypersensitivity in some patients.
U.S. Pat. No. 6,028,108 discloses a sterile oil-in-water emulsion of propofol and an amount of pentetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination. U.S. Pat. No. 6,177,477 discloses a sterile oil-in-water emulsion of propofol and an amount of tromethamine (T1US) sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination.
There is a continuing need to find a suitable preservative for use in the oil-in-water emulsion containing propofol. We surprisingly discovered inclusion of an amount of lipophilic organic compound (butylated hydroxytoluene, butylated hydroxyanisole) or its pharmaceutically acceptable salts thereof in a propofol oil-in-water emulsion is highly effective in preventing significant growth of a wide range of different microorganisms, including Gram (+) and Gram (−) bacteria as well as yeast and fungi, for at least 24 hours after adventitious contamination.
Many compounds varying dramatically in structure are known to serve as conventional preservatives. Depending upon the intended application or use of a product, a particular preservative is generally preferred. For example, conventional preservatives for food use are generally different than preservatives for cosmetic use, which in turn are generally different than preservatives for pharmaceutical use. Exemplary conventional preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, chlorobutanol, chlorocresol, methyl, ethyl and phenol, phenoxyethanol, propyl gallate, sorbic acid, benzyl alcohol, EDTA, pentetate, abide, organic solvent (such as glycol, propylene glycol, or polyethylene glycol), peroxide, ozone, chlorite, sodium bisulfite, potassium metabisulfite, potassium sulfite, sodium sulfite, and others known to those of ordinary skill in the art.